Processes for preparing pyrazolo[3,4-d]pyrimidine ethers

ABSTRACT

The present invention relates to processes for preparing pyrazolo[3,4-d]pyrimidine ether compounds that are modulators of glucose metabolism and therefore useful in the treatment of metabolic disorders such as diabetes and obesity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Ser. No. 60/643,712, filedJan. 13, 2005, the disclosure of which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to processes for preparingpyrazolo[3,4-d]pyrimidine ether compounds that are modulators of glucosemetabolism and therefore useful in the treatment of metabolic disorderssuch as diabetes and obesity.

BACKGROUND OF THE INVENTION

Modulation of G-protein coupled receptors has been well-studied forcontrolling various metabolic disorders. Small molecule modulators ofthe receptor RUP3, a G-protein coupled-receptor described in, forexample, GenBank (see, e.g., accession numbers XM_(—)066873 andAY288416), have been shown to be useful for treating or preventingcertain metabolic disorders. In particular, pyrazolo[3,4-d]pyrimidineethers and similar compounds, which are described in U.S. Ser. No.10/890,549 are shown to be effective modulators of the RUP3 receptor andare useful in the treatment of various metabolic-related disorders suchas type I diabetes, type II diabetes, inadequate glucose tolerance,insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia or syndrome X. The aromatic ethersare also useful in controlling weight gain, controlling food intake, andinducing satiety in mammals. The promising nature of these RUP3modulators in treating or preventing a number of common diseasesevidences a need for more efficient processes of making these compounds.The processes described herein are directed toward this and othercurrent needs.

SUMMARY OF THE INVENTION

The present invention provides, inter alia, processes for preparingcompounds of Formula I:

wherein constituent variables are provided herein; comprising reacting acompound of Formula II:

with a compound of Formula III:

in the presence of a trisubstituted phosphine and a compound having theFormula A′:

wherein R′ and R″ are each, independently, C₁₋₁₀ alkyl or C₃₋₇cycloalkyl; to form the compound of Formula I.

The present invention further provides processes for preparing compoundsof Formula II; by reacting a compound of Formula IV:

with R⁵CO₂H to form the compound of Formula II.

The present invention further provides a process for preparing acompound of Formula IV by reacting a compound of Formula V:

with a compound of Formula VI:

thereby forming the compound of Formula IV.

The present invention further provides processes for preparing compoundsof Formula I by reacting a compound of Formula IIa:

wherein constituent variables are provided herein, with a compound ofFormula III in the presence of base, to form the compound of Formula I.

The present invention further provides processes for preparing compoundsof Formula IIa by reacting a compound of Formula II with a halogenatingreagent to form the compound of Formula IIa.

The present invention further provides bulk samples of compoundsprepared by the processes described herein

DETAILED DESCRIPTION

The present invention is directed to processes and intermediates for thepreparation of aromatic ethers that are useful as RUP3 modulators forthe treatment of metabolic disorders such as diabetes and obesity.

Example processes and intermediates of the present invention areprovided below in Schemes I and II, wherein constituent members of theformulae depicted therein are defined below.

The present invention provides processes, such as exemplified in SchemesI and II, involving compounds of Formulas I, II, IIa, III, IV, V, and VIor salt forms thereof, wherein:

X is halo;

R is C₁₋₄ alkyl;

R¹ is C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl, orhalogen;

R² is —R²⁴, —CR²⁵R²⁶C(O)—R²⁴, —C(O)CR²⁵R²⁶—R²⁴, —C(O)—R²⁴,—CR²⁵R²⁶C(O)NR²⁷—R²⁴, —NR²⁷C(O)CR²⁵R²⁶—R²⁴, —C(O)NR²⁵—R²⁴,—NR²⁵C(O)—R²⁴, —C(O)O—R²⁴, —OC(O)—R²⁴, —C(S)—R²⁴, —C(S)NR²⁵—R²⁴,—NR²⁵C(S)—R²⁴, —C(S)O—R²⁴, —OC(S)—R²⁴, —CR²⁵R²⁶—R²⁴, or —S(O)₂—R²⁴;

R³ is H, C₁₋₈ alkyl or C₃₋₇ cycloalkyl, wherein said C₁₋₈ alkyl isoptionally substituted with C₁₋₄ alkoxy, C₃₋₇ cycloalkyl, or heteroaryl;

R⁵ and R¹⁰ are each, independently, H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino,carboxamide, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylsulfonamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl,hydroxylamino or nitro; wherein said C₂₋₆ alkenyl, C₁₋₈ alkyl, C₂₋₆alkynyl and C₃₋₆ cycloalkyl are optionally substituted with 1, 2, 3 or 4substituents selected from C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₄alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino andnitro;

R¹³ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₄ alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, arylsulfonyl, carbamimidoyl, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide,guanidinyl, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,heterocyclic, heterocyclic-oxy, heterocyclicsulfonyl,heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, hydroxyl, nitro,C₄₋₇ oxo-cycloalkyl, phenoxy, phenyl, sulfonamide, sulfonic acid, orthiol; and wherein said C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy,C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylsulfonamide, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, arylsulfonyl, carbamimidoyl, C₂₋₆ dialkylamino,heterocyclic, heterocyclic-carbonyl, heteroaryl, phenoxy and phenyl areoptionally substituted with 1 to 5 substituents selected from C₁₋₅ acyl,C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino,C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heteroaryl, heterocyclic,hydroxyl, nitro, phenyl, and phosphonooxy; and wherein said C₁₋₇ alkyland C₁₋₄ alkylcarboxamide are each optionally substituted with 1 to 5substituents selected from C₁₋₄ alkoxy and hydroxy; or

R¹³ is a group of Formula (A):

R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each, independently, H, C₁₋₅ acyl, C₁₋₅acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide,C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl or nitro; or

two adjacent R¹⁴, R¹⁵, R¹⁶ and R¹⁷ together with the atoms to which theyare attached form a 5-, 6- or 7-membered fused cycloalkyl, cycloalkenylor heterocyclic group, wherein said 5-, 6- or 7-membered fused group isoptionally substituted with halogen;

R¹⁸ is H, C₁₋₅ acyl, C₂₋₆ alkenyl, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide,C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen,heteroaryl or phenyl, and wherein said heteroaryl or phenyl isoptionally substituted with 1 to 5 substituents selected independentlyfrom C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈dialkylamino, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl and hydroxyl;

R²⁴ is H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, orheterocyclic each optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, heterocyclic, hydroxyl, hydroxylamino, nitro, phenyl,phenoxy, and sulfonic acid, wherein said C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylamino, heteroaryl, phenyl and phenoxy are each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino,C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide,C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄alkylthioureyl, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino, nitro, and phenyl;

R²⁵, R²⁶ and R²⁷ are each, independently, H or C₁₋₈ alkyl;

m is 0, 1, 2, 3,or 4;

n is 0 or 1; and

p and r are each, independently, 0, 1, 2 or 3.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (e.g., n,m, R₁, R₂, R₃, R₅, R₁₀, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, etc.) contained withinthe generic chemical formulae described herein [e.g. I, (A), A′, II,III, IV, V, etc.] and process steps disclosed herein are specificallyembraced by the present invention just as if they were explicitlydisclosed, to the extent that such combinations embrace compounds thatresult in stable compounds (ie., compounds that can be isolated,characterized and tested for biological activity). In addition, allsubcombinations of the chemical groups listed in the embodimentsdescribing such variables, as well as all subcombinations of processsteps, are also specifically embraced by the present invention just asif each of such subcombination of chemical groups and process steps wereexplicitly disclosed herein.

In some embodiments, n is 1.

In some embodiments, m is 0.

In some embodiments, R² is —C(O)O—R²⁴.

In some embodiments, R² is —C(O)O—R²⁴ and R²⁴ is C₁₋₈ alkyl or C₃₋₇cycloalkyl.

In some embodiments, R² is —C(O)O—R²⁴ and R²⁴ is C₁₋₄ alkyl.

In some embodiments, R² is —C(O)O—R²⁴ and R²⁴ is methyl, ethyl, orprop-1-yl, prop-2-yl.

In some embodiments, R² is —C(O)O—R²⁴ and R²⁴ is prop-2-yl.

In some embodiments, R³ is H.

In some embodiments, R⁵ is H.

In some embodiments, R¹⁰ is H.

In some embodiments, R¹³ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, arylsulfonyl,carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, guanidinyl, halogen,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclic, heterocyclic-oxy,heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl,heteroarylcarbonyl, hydroxyl, nitro, C₄₋₇ oxo-cycloalkyl, phenoxy,phenyl, sulfonamide, sulfonic acid, or thiol.

In some embodiments, R¹³ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, or C₁₋₄ alkylsulfonyl.

In some embodiments, R¹³ is C₁₋₄ alkylsulfinyl or C₁₋₄ alkylsulfonyl.

In some embodiments, R¹³ is C₁₋₄ alkylsulfonyl.

In some embodiments, R¹³ is methylsulfonyl or ethylsulfonyl.

In some embodiments, R¹³ is methylsulfonyl.

In some embodiments, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each, independently, H,C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₂₋₆ alkynyl, cyano, halogen,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, hydroxyl, or nitro.

In some embodiments, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each, independently, H,C₁₋₄ alkoxy, C₁₋₈ alkyl, cyano, halogen, hydroxyl, or nitro.

In some embodiments, R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each, independently, Hor halogen.

In some embodiments, R¹⁴ is other than H.

In some embodiments, R¹⁴ is halogen.

In some embodiments, R¹⁴ is F.

In some embodiments, R¹⁵, R¹⁶, and R¹⁷ are each H and R¹⁴ is other thanH.

In some embodiments, R¹³ is C₁₋₄ alkylsulfonyl; R¹⁵, R¹⁶, and R¹⁷ areeach H; and R¹⁴ is halogen.

In some embodiments, R is methyl or ethyl;

In some embodiments, R is ethyl;

In some embodiments, X is Cl;

In some embodiments:

R² is —C(O)O—R²⁴;

R³is H;

R⁵is H;

R¹⁰ is H;

R¹³ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, arylsulfonyl, carbamimidoyl, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide,guanidinyl, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,heterocyclic, heterocyclic-oxy, heterocyclicsulfonyl,heterocyclic-carbonyl, heteroaryl, heteroarylcarbonyl, hydroxyl, nitro,C₄₋₇ oxo-cycloalkyl, phenoxy, phenyl, sulfonamide, sulfonic acid, orthiol;

R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each, independently, H, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₂₋₆ alkynyl, cyano, halogen, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, hydroxyl, or nitro;

n is 1; and

m is 0.

In some embodiments:

R² is —C(O)O—R²⁴;

R³is H;

R⁵ is H;

R¹⁰ is H;

R¹³ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, or C₁₋₄ alkylsulfonyl;

R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each, independently, H, C₁₋₄ alkoxy, C₁₋₈alkyl, cyano, halogen, hydroxyl, or nitro;

n is 1; and

m is 0.

In some embodiments:

R² is —C(O)O—R²⁴;

R³ is H;

R⁵ is H;

R¹⁰ is H;

R¹³ is C₁₋₄ alkylsulfinyl or C₁₋₄ alkylsulfonyl;

R¹⁴ is halo;

R¹⁵, R¹⁶, and R¹⁷ are each H;

R²⁴ is methyl, ethyl, or prop-1-yl, prop-2-yl;

n is 1; and

m is 0.

In some embodiments:

R² is —C(O)O—R²⁴;

R³ is H;

R⁵ is H;

R¹⁰ is H;

R¹³ is methylsulfonyl;

R¹⁴is F;

R¹⁵, R¹⁶, and R¹⁷ are each H;

R²⁴ is prop-2-yl;

n is 1; and

m is 0.

Embodiments of Scheme I

The present invention provides, inter alia, processes for preparingcompounds of Formula I:

by reacting a compound of Formula II:

with a compound of Formula III:

in the presence of a trisubstituted phosphine and a compound having theFormula A′:

wherein R′ and R″ are each, independently, C₁₋₁₀ alkyl or C₃₋₇cycloalkyl; to form the compound of Formula I.

The trisubstituted phosphine can be any suitable tertiary phosphine suchas a phosphine having the formula P(R)₃, where each R is, independently,C₁₋₈ alkyl, aryl, cycloalkyl, heteroaryl, heterocyclic, arylalkyl,cycloalkylalkyl, heteroarylalkyl, or heterocyclicalkyl, each of whichcan be substituted by one or more halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxy, or C₁₋₄ haloalkoxy. In some embodiments, the trisubstitutedphosphine is a triarylphosphine. In some embodiments, the trisubstitutedphosphine is triphenylphosphine.

A suitable compound of Formula A′ can be readily selected by the skilledartisan. In some embodiments, R′ and R″ are each, independently, C₁₋₁₀alkyl. In further embodiments, R′ and R″ are each, independently, C₁₋₄alkyl. In yet further embodiments, R′ and R″ are both prop-2-yl.

In some embodiments, the compound of Formula III is added to a mixturecontaining the compound of Formula II, the compound of Formula A′, andthe trisubstituted phosphine. Additional portions of phosphine and/oradditional portions of the compound of Formula A′ can be added after theinitial reacting. In some embodiments, the total amount of phosphine isadded in two or more portions. In some embodiments, the total amount ofcompound of Formula A′ is added in two or more portions.

The reacting of II with III can be carried out at any suitabletemperature. In some embodiments, the reacting is carried out at atemperature of about 35 to about 65, about 40 to about 60, or about 45to about 55° C.

The reacting of II with III can also be optionally carried out in asolvent. Suitable solvents can be readily selected by the skilledartisan. Example solvents include polar to moderately polar solvents orhigh boiling solvents such as dimethylformamide (DMF), dimethylacetamide(DMA), toluene, acetonitrile, propionitrile, tetrahydrofuran (THF),N-methylpyrrolidine (NMP), or tertiary amines including cyclic amines.In some embodiments, the solvent includes a cyclic amine. In someembodiments, the cyclic amine is an N-alkylated morpholine such as4-methylmorpholine.

The reacting of II with III can be carried out where the molar ratio ofcompound of Formula A′ to compound of Formula II is about 2:1 to about1:1, about 1.8:1 to about 1.2:1; or about 1.8:1 to about 1.5:1. In someembodiments, the molar ratio of trisubstituted phosphine to compound ofFormula II is about about 2:1 to about 1:1, 1.8:1 to about 1.2:1, orabout 1.8:1 to about 1.5:1. In further embodiments, the molar ratio ofcompound of Formula A′ to trisubstituted phosphine is about 1:1. In yetfurther embodiments, the molar ratio of compound of Formula II tocompound of Formula III is about 1:1.

In some embodiments, the reacting of II with III can result in theformation of a byproduct which is a structural isomer (e.g., has thesame molecular weight) of the compound of Formula I. Accordingly, bulksamples of Formula I made by the processes described herein can containa compound which is a structural isomer of the compound of Formula I.The amount of structural isomer byproduct in preparations of Formula Ican be, for example, less than about 5%, less than about 3%, less thanabout 2%, less than about 1%, less than about 0.5%, less than about0.2%, less than about 0.1%, less than about 0.05%, less than about0.02%, or less than about 0.01% by weight in the bulk sample.

The present invention further provides processes for preparing acompound of Formula II by reacting a compound of Formula IV:

with R⁵C₂H to form the compound of Formula II.

The reacting of IV with acid R⁵CO₂H can be optionally carried out in thepresence of any suitable solvent readily selected by the skilledartisan. In some embodiments, the solvent is a polar solvent and/or ahigh boiling solvent (e.g., boils above 100° C). Example suitablesolvents include an aqueous solvent (water or water mixture containinggreater than about 5 wt % water), dimethylsulfoxide (DMSO),dimethylformamide (DMF), dimethylacetamide (DMA), N-methylpyrrolidine(NMP), propionitrile, and the like. In some embodiments, the solvent isan aqueous solvent such as water.

The reacting of IV with acid R⁵CO₂H can be optionally carried out in thepresence of a strong acid, for example, sulfuric acid. In someembodiments, the strong acid is present from about 0.5 equivalents toabout 3 equivalents compared to a compound of Formula IV. In furtherembodiments, the strong acid is present from about 1 equivalent to about2.5 equivalents compared to a compound of Formula IV. In yet furtherembodiments, the strong acid is present in about 2 equivalents comparedto a compound of Formula IV. In certain embodiments, the presence of thestrong acid reduces the reaction time by a factor of about 7 to about 4compared to the reaction time in the absence of strong acid.

The reacting of IV with acid R⁵CO₂H can be carried out at any suitabletemperature. For example, the reaction can be carried out at elevatedtemperature for at least a portion of the reacting. In some embodiments,the temperature is reflux temperature. In further embodiments, thereaction is carried out at a temperature of about 80 to about 120° C. Inyet further embodiments, the reaction is carried out at a temperature ofabout 80 to about 120° C. and then the resulting mixture is cooled toabout −20 to about 20° C. The cooling process can be relatively rapid,cooling the mixture in less than about 2, less than about 1, or lessthan about 0.5 hours.

While not wishing to be bound by theory, it is believed that therelatively rapid cooling substantially prevents or inhibits thehydrolysis of the bicyclic product II, which is a competing reactionthat appears to be favored at intermediate temperatures (e.g., 70-80°C). An example byproduct of hydrolysis of II is shown in Formula IIb:

In some embodiments, bulk samples of the compound of Formula II made bythe processes described herein can contain a detectable amount ofcompound of Formula IIb. The amount of compound of Formula IIb inpreparations of Formula II can be, for example, less than about 5%, lessthan about 3%, less than about 2%, less than about 1%, less than about0.5%, less than about 0.2%, less than about 0.1%, less than about 0.05%,less than about 0.02%, or less than about 0.01% by weight of the bulksample.

Because the byproduct of Formula IIb can be carried over to preparationsof Formula I, bulk samples of Formula I made by the processes describedherein can contain a detectable amount of compound of Formula IIb. Theamount of compound of Formula IIb in preparations of Formula I can be,for example, less than about 5%, less than about 3%, less than about 2%,less than about 1%, less than about 0.5%, less than about 0.2%, lessthan about 0.1%, less than about 0.05%, less than about 0.02%, or lessthan about 0.01% by weight.

The compound of Formula IIb and other byproducts can be detected andquantified by routine methods including, for example, proton nuclearmagnetic resonance, high performance liquid chromatography, massspectrometry, and the like. The amount of compound of Formula IIb andother byproducts in bulk samples prepared according to the processesherein can be reduced or substantially eliminated by routine methodssuch as recrystallization or chromatography techniques.

The term “bulk sample” is used herein consistently with its meaning inthe art which, for example, refers to an amount of product preparedaccording to a given process or procedure. Bulk samples can be any size,but typically range from about 1 mg on upward to several thousands ofkilograms or more.

The reacting of IV with acid R⁵CO₂H can further be carried out whereinthe R⁵CO₂H is provided in molar excess relative to the compound ofFormula IV. In some embodiments, the molar ratio of acid R⁵CO₂H tocompound of Formula IV is about 100:1 to about 2:1; about 70:1 to about10:1; about 50:1 to about 30:1, about 45:1 to about 35:1, or about 40:1.In some embodiments, the acid R⁵CO₂H is added in two or more portions.In some instances when, for example, the reaction is conducted atelevated temperature, a volatile acid or ester thereof may distill away.Thus, additional amounts of acid can be added periodically to maintain amolar excess with respect to the compound of Formula IV.

In the reacting of R⁵CO₂H with the compound of Formula IV, the reactioncan be carried out for a duration until product of Formula II isdetected. In some embodiments, the reaction is carried out until greaterthan about 50, greater than about 75, greater than about 80, greaterthan about 90, greater than about 95, greater than about 97, greaterthan about 98 or greater than about 99, greater than about 99.5% (e.g.,mol %) of the compound of Formula IV is converted to the compound ofFormula II. The conversion can be quantitated and/or monitored by anysuitable method routine in the art such as by HPLC.

The present invention further provides a process for preparing acompound of Formula IV by reacting a compound of Formula V:

with a compound of Formula VI:

thereby forming the compound of Formula IV.

The reacting of the compound of Formula V with the malonitrile ofFormula VI can be optionally carried out in a solvent. Any suitablesolvent can be selected by the skilled artisan. In some embodiments, thesolvent is an alcohol such as methanol, ethanol, n-propanol,isopropanol, n-butanol, and the like. In some embodiments, the solventis methanol.

The reacting of the compound of Formula V with the malonitrile ofFormula VI can be optionally carried out in the absence of a base.Example bases which can be absent include alkoxides such as methoxide orethoxide (e.g., provided as alkali metal or other salts thereof).

Further, the reacting of the compound of Formula V with the malonitrileof Formula VI can be carried out where the molar ratio of the compoundof Formula V to the malonitrile of Formula VI is about 1:2 to about 1:1,about 1:1.5 to about 1:1, about 1:1.2 to about 1:1, or about 1:1.1.

Reaction between the compound of Formula V and the malonitrile ofFormula VI can be carried out at any suitable temperature readilyselected by the art skilled. For example, the reaction can be carriedout at a temperature less than 0° C. such as at about −20 to about 10 orabout −10 to about 0° C.

The compounds of Formulas III, IV, and V can be prepared according toroutine methods in the art. Example preparations of these compounds areprovided in U.S. Ser. No. 10/890,549, which is incorporated herein byreference in its entirety.

Embodiments of Scheme II

The present invention further provides processes for preparing compoundsof Formula I by reacting a compound of Formula IIa:

with a compound of Formula III in the presence of a base, to form thecompound of Formula I.

The base can be any suitable base readily selected by the skilledartisan. For example, the base can be an alkoxide salt. Any suitablealkoxide salt can be used such as, for example, alkali metal or othersalts of methoxide, ethoxide, propoxide, isopropoxide, n-butoxide,isobutoxide, t-butoxide, and the like. In some embodiments, the alkoxidesalt is an alkali metal alkoxide. In some embodiments, the alkoxide saltis a t-butoxide salt. In some embodiments, the alkoxide salt is sodiumt-butoxide. Other suitable bases include, for example, alkali metalhydrides (e.g., NaH), alkali metal amides (e.g., sodamide), alkali metalcarbonates (e.g., Na₂CO₃, K₂CO₃, etc.), and the like.

The reacting of the compound of Formula IIa with the compound of FormulaIII can be optionally carried out in a solvent. A suitable solvent canbe readily selected by the skilled artisan. For example, the solvent canbe an aromatic solvent such as benzene, toluene, nitrobenzene,chlorobenzene, and the like. In some embodiments, the solvent includestoluene. Other suitable solvents include polar to moderately polarsolvents or high boiling solvents such as dimethylformamide (DMF),dimethylacetamide (DMA), toluene, acetonitrile, propionitrile,tetrahydrofuran (THF), N-methylpyrrolidine (NMP), or tertiary aminesincluding cyclic amines such as an N-alkylated morpholine (e.g.,4-methylmorpholine).

Further, the reacting of the compound of Formula IIa with the compoundof Formula III can be optionally carried out for at least a portion ofthe time at a temperature below about 40, below about 30, below about20, or below about 15° C.

In some embodiments, the molar ratio of the compound of Formula III tothe compound of Formula IIa is about 2:1 to about 1:1, about 1.5:1 toabout 1:1 or about 1.2:1. In further embodiments, the molar ratio ofalkoxide salt to the compound of Formula IIa is about 2:1 to about 1:1,about 1.5:1 to about 1:1, about 1.3:1 to about 1:1, or about 1.3:1.

The present invention further provides processes for preparing compoundsof Formula IIa by reacting a compound of Formula II with a halogenatingreagent to form the compound of Formula IIa.

The halogenating reagent can be any reagent capable of halogenating thecompound of Formula IIa. Any of numerous halogenating reagents are knownin the art. In some embodiments, the halogenating reagent is abrominating or chlorinating reagent. Some example brominating reagentsinclude, for example, Br₂, N-bromosuccinimide (NBS),1,3-dibromo-5,5-dimethylhydantoin, pyridinium tribromide (pyrHBr₃),POBr₃, and the like. Example chlorinating reagents includeN-chlorosuccinimide, POCl₃, and the like. In some embodiments, thehalogenating reagent is POX3 where X is halo such as Cl or Br. In someembodiments, the halogenating reagent is POCl₃.

The reacting of a compound of Formula II with a halogenating reagent canbe optionally carried out in the presence of a catalyst. In someembodiments, the catalyst includes a di-substituted amide such as acompound having the Formula R^(cat)C(O)N(R′)(R″) wherein R^(cat) is H,C₁₋₈ alkyl, aryl, heteroaryl, and the like; and each R′ and R″ is,independently, C₁₋₈ alkyl. In further embodiments, the di-substitutedamide is dimethylformamide (DMF) or dimethylacetamide (DMA). In someembodiments, the di-substituted amide is DMF.

The reacting of a compound of Formula II with a halogenating reagent canbe optionally carried out at an elevated temperature. For example, thereaction mixture can be heated to reflux. In some embodiments, thetemperature for at least a portion of the reaction time can be about 80to about 140° C.

In some embodiments, the halogenating reagent can be provided in molarexcess relative to the amount of compound of Formula II. For example,the molar ratio of halogenating reagent to the amount of compound ofFormula II can be about 50:1 to about 2:1, about 25:1 to about 2:1, orabout 15:1 to about 7:1. In some embodiments, the molar ratio ofcompound of Formula II to amount of catalyst is about 2:1 to about 1:1,about 1.5:1 to about 1:1, or about 1.3:1 to about 1.2:1. In someembodiments, the catalyst is added to the reaction mixture in two ormore portions. In further embodiments, the portions of catalyst aresubstantially equal in amount.

Definitions

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

The term “C_(i-j)” denotes the number of carbon atoms in the moiety towhich the term refers. For example, C₁₋₈ alkyl (where i is 1 and j is 8)refers to an alkyl group having 1 (C₁), 2 (C₂), 3 (C₄), 5 (C₅), 6 (C₆),7 (C₇), or 8 (C₈) carbon atoms.

The term “acyl” denotes a carbonyl (C═O) substituted by an alkylradical, wherein the definition of alkyl has the same definition asdescribed herein. Some examples include, but are not limited to, acetyl,propionyl, n-butanoyl, iso-butanoyl, sec-butanoyl, t-butanoyl (i.e.,pivaloyl), pentanoyl and the like.

The term “acyloxy” denotes —O— substituted by an acyl radical, whereinacyl has the same definition has described herein. Some examples includebut are not limited to acetyloxy, propionyloxy, butanoyloxy,iso-butanoyloxy, sec-butanoyloxy, t-butanoyloxy and the like.

The term “acylsulfonamide” refers to a sulfonamide substituted by acylon the sulfonamide N-atom, wherein the definitions for acyl andsulfonamide have the same meaning as described herein, and anacylsulfonamide can be represented by the following formula:

Some embodiments of the present invention include C₁₋₅ acylsulfonamide,C₁₋₄ acylsulfonamide, C₁₋₃ acylsulfonamide, or C₁₋₂ acylsulfonamide.Examples of acylsulfonamides include, but are not limited to,acetylsulfamoyl [—S(═O)₂NHC(═O)Me], propionylsulfamoyl[—S(═O)₂NHC(═O)Et], isobutyrylsulfamoyl, butyrylsulfamoyl,2-methyl-butyrylsulfamoyl, 3-methyl-butyrylsulfamoyl,2,2-dimethyl-propionylsulfamoyl, pentanoylsulfamoyl,2-methyl-pentanoylsulfamoyl, 3-methyl-pentanoylsulfamoyl,4-methyl-pentanoylsulfamoyl, and the like.

The term “alkenyl” denotes an alkyl radical containing having at leastone carbon-carbon double bond. In some embodiments, the alkenyl group isC₂₋₆ alkenyl, C₂₋₅ alkenyl, C₂₋₄ alkenyl, C₂₋₃ alkenyl or C₂ alkenyl.Both E and Z isomers are embraced by the term “alkenyl.” Furthermore,the term “alkenyl” includes groups with 1, 2, 3, 4 or more double bonds.Accordingly, if more than one double bond is present then the bonds maybe all E or Z or a mixtures of E and Z. Examples of an alkenyl includevinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl, 2,4-hexadienyl and the like.

The term “alkoxy” as used herein denotes a radical alkyl, as definedherein, attached directly to an oxygen atom. Examples include methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy,sec-butoxy and the like.

The term “alkyl” denotes a straight or branched hydrocarbon radical. Insome embodiments, the alkyl group contains 1 to 8 carbons, 1 to 7carbons, 1 to 6 carbons, 1 to 5 carbons, 1 to 4 carbons, 1 to 3 carbons,1 or 2 carbons. Examples of alkyl groups include, but are not limitedto, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,t-butyl, pentyl, iso-pentyl, t-pentyl, neo-pentyl, 1-methylbutyl [i.e.,—CH(CH₃)CH₂CH₂CH₃], 2-methylbutyl [i.e., —CH₂CH(CH₃)CH₂CH₃], n-hexyl andthe like.

The term “alkylcarboxamido” or “alkylcarboxamide” denotes a single alkylgroup attached to the nitrogen or carbon of an amide group, whereinalkyl has the same definition as found herein. The alkylcarboxamide maybe represented by the following:

Examples include, but are not limited to, N-methylcarboxamide,N-ethylcarboxamide, N-n-propylcarboxamide, N-iso-propylcarboxamide,N-n-butylcarboxamide, N-sec-butylcarboxamide, N-iso-butylcarboxamide,N-t-butylcarboxamide and the like.

The term “alkylene” refers to a divalent alkyl group. In someembodiments, alkylene refers to, for example, —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, and the like. In some embodiments, alkylene refers to —CH—,—CHCH₂—, —CHCH₂CH₂—, and the like wherein these examples relategenerally to “A”.

The term “alkylsulfinyl” denotes —S(O)— substituted by alkyl, whereinthe alkyl radical has the same definition as described herein. Examplesinclude, but not limited to, methylsulfinyl, ethylsulfinyl,n-propylsulfinyl, iso-propylsulfinyl, n-butylsulfinyl,sec-butylsulfinyl, iso-butylsulfinyl, t-butyl, and the like.

The term “alkylsulfonamide” refers to the groups

wherein alkyl has the same definition as described herein.

The term “alkylsulfonyl” denotes —S(O)₂— substituted by alkyl, whereinthe alkyl radical has the same definition as described herein. Examplesinclude, but are not limited to, methylsulfonyl, ethylsulfonyl,n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl,sec-butylsulfonyl, iso-butylsulfonyl, t-butyl, and the like.

The term “alkylthio” denotes —S— substituted by alkyl, wherein the alkylradical has the same definition as described herein. Examples include,but not limited to, methylsulfanyl (i.e., CH₃S—), ethylsulfanyl,n-propylsulfanyl, iso-propylsulfanyl, n-butylsulfanyl,sec-butylsulfanyl, iso-butylsulfanyl, t-butyl, and the like.

The term “alkylthiocarboxamide” denotes a thioamide of the followingformulae:

wherein alkyl has the same definition as described herein.

The term “alkylthioureyl” denotes the group of the formula: —NC(S)N—wherein one or both of the nitrogens are substituted with the same ordifferent alkyl groups, and alkyl has the same definition as describedherein. Examples of an alkylthioureyl include, but are not limited to,CH₃NHC(S)NH—, NH₂C(S)NCH₃—, (CH₃)₂N(S)NH—, (CH₃)₂N(S)NH—,(CH₃)₂N(S)NCH₃—, CH₃CH₂NHC(S)NH—, CH₃CH₂NHC(S)NCH₃—, and the like.

The term “alkylureyl” denotes the group of the formula: —NC(O)N— whereinone are both of the nitrogens are substituted with the same or differentalkyl group, wherein alkyl has the same definition as described herein.Examples of an alkylureyl include, but not limited to, CH₃NHC(O)NH—,NH₂C(O)NCH₃—, (CH₃)₂N(O)NH—, (CH₃)₂N(O)NH—, (CH₃)₂N(O)NCH₃—,CH₃CH₂NHC(O)NH—, CH₃CH₂NHC(O)NCH₃—, and the like.

The term “alkynyl” denotes an alkyl group having at least onecarbon-carbon triple bond. In some embodiments, the alkynyl group has 2to 8 carbons, 2 to 7 carbons, 2 to 6 carbons, 2 to 5 carbons, 2 to 4carbons, 2 to 3 carbons, or 2 carbons. Examples of alkynyl groupsinclude, but are not limited to, ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl andthe like. Additionally, an alkynyl group can have 1, 2, 3, 4 or moretriple bonds, forming for example, di- and tri-ynes.

The term “amino” denotes the group —NH₂.

The term “alkylamino” denotes amino substituted by alkyl, wherein thealkyl radical has the same meaning as described herein. Some examplesinclude, but not limited to, methylamino, ethylamino, n-propylamino,iso-propylamino, n-butylamino, sec-butylamino, iso-butylamino,t-butylamino, and the like.

The term “aryl” denotes monocyclic or polycyclic aromatic hydrocarbonssuch as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl,indanyl, indenyl, and the like. In some embodiments, aryl groups havefrom 6 to about 20 carbon atoms.

The term “arylalkyl” denotes alkyl substituted with an aryl group.Examples of an “arylalkyl” include benzyl, phenethylene and the like.

The term “arylcarboxamido” denotes an amide group substituted by an arylgroup on the N-atom, wherein aryl has the same definition as foundherein. An example is N-phenylcarboxamide.

The term “arylureyl” denotes the group —NC(O)N— where one of thenitrogens are substituted with an aryl.

The term “benzyl” denotes the group —CH₂C₆H₅.

The term “carbamimidoyl” refers to a group of the following chemicalformula:

and in some embodiments, one or both hydrogens are replaced with anothergroup. For example, one hydrogen can be replaced with a hydroxyl groupto give a N-hydroxycarbamimidoyl group, or one hydrogen can be replacedwith an alkyl group to give N-methylcarbamimidoyl, N-ethylcarbamimidoyl,N-propylcarbamimidoyl, N-butylcarbamimidoyl, and the like.

The term “carboalkoxy” refers to an alkyl ester of a carboxylic acid,wherein the alkyl group is as defined herein. Examples include, but notlimited to, carbomethoxy, carboethoxy, carbopropoxy, carboisopropoxy,carbobutoxy, carbo-sec-butoxy, carbo-iso-butoxy, carbo-t-butoxy,carbo-n-pentoxy, carbo-iso-pentoxy, carbo-t-pentoxy, carbo-neo-pentoxy,carbo-n-hexyloxy, and the like.

The term “carboxamide” refers to the group —CONH₂.

The term “carboxy” or “carboxyl” denotes the group —CO₂H; also referredto as a carboxylic acid group.

The term “cyano” denotes the group —CN.

The term “cycloalkenyl” denotes a non-aromatic ring radical containing 3to 6 ring carbons and at least one double bond; some embodiments contain3 to 5 carbons; some embodiments contain 3 to 4 carbons. Examplesinclude cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentenyl,cyclohexenyl, and the like.

The term “cycloalkyl” denotes a saturated, cyclic hydrocarboncontaining, for example, 3 to 14, 1 to 10, 3 to 8, 3 to 7, 3 to 6, 3 to5, or 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclopenyl, cyclohexyl, cycloheptyl and the like.

The term “cycloalkylalkyl” denotes an alkyl group substituted by acycloalkyl group.

The term “cycloalkylene” refers to a divalent cycloalkyl radical. Insome embodiments, the two bonding groups are on the same carbon, forexample:

In some embodiments, the two bonding groups are on different carbons.

The term “diacylamino” denotes an amino group substituted with two acylgroups, wherein the acyl groups may be the same or different, such as:

Examples of diacylamino groups include, but limited to, diacetylamino,dipropionylamino, acetylpropionylamino and the like.

The term “dialkylamino” denotes an amino group substituted with two ofthe same or different alkyl radicals, wherein alkyl has the samedefinition as described herein. Some examples include, but not limitedto, dimethylamino, methylethylamino, diethylamino, methylpropylamino,methylisopropylamino, ethylpropylamino, ethylisopropylamino,dipropylamino, propylisopropylamino and the like.

The term “dialkylcarboxamido” or “dialkylcarboxamide” denotes an amidesubstituted by two alkyl radicals, that are the same or different.Dialkylcarboxamidos can be represented by the following groups:

Examples of dialkylcarboxamides include, but are not limited to,N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide,N,N-diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the like.

The term “dialkylsulfonamide” refers to one of the following groupsshown below:

Examples include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, and the like.

The term “dialkylthiocarboxamido” or “dialkylthiocarboxamide” denotes athioamide substituted by two alkyl radicals, that are the same ordifferent, wherein alkyl has the same definition as described herein.Example dialkylthiocarboxamido groups can be represented by thefollowing groups:

Examples of dialkylthiocarboxamides include, but are not limited to,N,N-dimethylthiocarboxamide, N-methyl-N-ethylthiocarboxamide and thelike.

The term “dialkylsulfonylamino” refers to an amino group substitutedwith two alkylsulfonyl groups as defined herein.

The term “ethynylene” refers to —C≡C—.

The term “formyl” refers to the group —CHO.

The term “guanidine” refers to a group of the following chemicalformula:

The term “haloalkoxy” denotes —O— substituted by haloalkyl. Examplesinclude, but are not limited to, difluoromethoxy, trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy, and the like.

The term “haloalkyl” denotes an alkyl group, as defined herein, whereinthe alkyl is substituted with one or more halogens. Examples ofhaloalkyl groups include, but are not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, chlorodifluoromethyl,2,2,2-trifluoroethyl, pentafluoroethyl and the like.

The term “haloalkylcarboxamide” denotes an alkylcarboxamide group,defined herein, substituted with one or more halogens.

The term “haloalkylsulfinyl” denotes sulfoxide —S(O)— substituted by ahaloalkyl radical, wherein the haloalkyl radical has the same definitionas described herein. Examples include, but are not limited to,trifluoromethylsulfinyl, 2,2,2-trifluoroethylsulfinyl,2,2-difluoroethylsulfinyl and the like.

The term “haloalkylsulfonyl” denotes —S(O)₂— substituted by a haloalkylradical, wherein haloalkyl has the same definition as described herein.Examples include, but not limited to, trifluoromethylsulfonyl,2,2,2-trifluoroethylsulfonyl, 2,2-difluoroethylsulfonyl and the like.

The term “haloalkylthio” denotes —S— substituted by a haloalkyl radical,wherein the haloalkyl has the same meaning as described herein. Examplesinclude, but not limited to, trifluoromethylthio (i.e., CF₃S—),1,1-difluoroethylthio, 2,2,2-trifluoroethylthio and the like.

The term “halogen” or “halo” denotes to a fluoro, chloro, bromo or iodogroup.

The term “heteroalkylene” refers to alkylene interrupted or appended bya heteroatom-containing group selected from O, S, S(O), S(O)₂ and NH.Some examples include, but not limited to, the groups of the followingformulae:

and the like.

The term “heteroaryl” denotes an aromatic ring system that may be asingle ring, two fused rings or three fused rings wherein at least onering carbon is a heteroatom selected from, but not limited to, the groupconsisting of O, S and N, wherein the N can be optionally substitutedwith H, O, C₁₋₄ acyl or C₁₋₄ alkyl. Examples of heteroaryl groupsinclude, but are not limited to, pyridyl, benzofuranyl, pyrazinyl,pyridazinyl, pyrimidinyl, triazinyl, quinoline, benzoxazole,benzothiazole, 1H-benzimidazole, isoquinoline, quinazoline, quinoxalineand the like. In some embodiments, the heteroatom is O, S, NH, examplesinclude, but not limited to, pyrrole, indole, and the like.

The term “heteroarylalkyl” denotes an alkyl group substituted by aheteroaryl group.

The term “heterocyclic” denotes a non-aromatic, cyclic hydrocarbon(i.e., cycloalkyl or cycloalkenyl as defined herein) wherein one or more(e.g., one, two or three) ring carbons are replaced by a heteroatomselected from, but not limited to, the group consisting of O, S, N,wherein the N can be optionally substituted with H, O, C₁₋₄ acyl or C₁₋₄alkyl, and ring carbon atoms are optionally substituted with oxo or asulfido thus forming a carbonyl or thiocarbonyl group. The heterocyclicgroup can be a 3-, 4-, 5-, 6- or 7-membered ring. Examples of aheterocyclic group include but not limited to aziridin-1-yl,aziridin-2-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl,piperidin-1-yl, piperidin-4-yl, morpholin-4-yl, piperzin-1-yl,piperzin-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, [1,3]-dioxolan-2-yl andthe like.

The term, “heterocyclicalkyl” denotes an alkyl group substituted by aheterocyclic group.

The term “heterocyclic-carbonyl” denotes a carbonyl group substituted bya heterocyclic group, as defined herein. In some embodiments, a ringnitrogen of the heterocyclic group is bonded to the carbonyl groupforming an amide. Examples include, but are not limited to,

and the like.In some embodiments, a ring carbon is bonded to the carbonyl groupforming a ketone group. Examples include, but are not limited to,

and the like.

The term “heterocyclic-oxy” refers —S— substituted by a heterocyclicgroup, as defined herein. Examples include the following:

and the like.

The term “heterocyclicsulfonyl” denotes SO₂ substituted with aheterocyclic group having a ring nitrogen, where the ring nitrogen isbonded directly to an SO₂ group forming an sulfonamide. Examplesinclude, but not limited to,

and the like.

The term “hydroxyl” refers to the group —OH.

The term “hydroxylamino” refers to the group —NHOH.

The term “nitro” refers to the group —NO₂.

The term “oxo-cycloalkyl” refers to cycloalkyl, as defined herein,wherein one of the ring carbons is replaced with a carbonyl. Examples ofoxo-cycloalkyl include, but are not limited to, 2-oxo-cyclobutyl,3-oxo-cyclobutyl, 3-oxo-cyclopentyl, 4-oxo-cyclohexyl, and the like andrepresented by the following structures respectively:

The term “perfluoroalkyl” denotes the group of the formula —C_(n)F₂₊₁.Examples of perfluoroalkyls include CF₃, CF₂CF₃, CF₂CF₂CF₃, CF(CF₃)₂,CF₂CF₂CF₂CF₃, CF₂CF(CF₃)₂, CF(CF₃)CF₂CF₃ and the like.

The term “phenoxy” refers to the group C₆H₅O—.

The term “phenyl” refers to the group C₆H₅—.

The term “phosphonooxy” refers to a group with the following chemicalstructure:

The term “sulfonamide” refers to the group —SO₂NH₂.

The term “sulfonic acid” refers to the group —SO₃H.

The term “tetrazolyl” refers to the five membered heteroaryl of thefollowing formulae:

In some embodiments, the tetrazolyl group is further substituted ateither the 1 or 5 position, resepectively, with a group selected fromthe group consisting of alkyl, haloalkyl and alkoxy.

The term “thiol” denotes the group —SH.

As used herein, the term “reacting” is used as known in the art andgenerally refers to the bringing together of chemical reagents in such amanner so as to allow their interaction at the molecular level toachieve a chemical or physical transformation of at least one chemicalreagent.

As used herein, the term “substituted” refers to the replacement of ahydrogen moiety with a non-hydrogen moiety in a molecule or group.

For compounds in which a variable appears more than once, each variablecan be a different moiety selected from the Markush group defining thevariable. For example, where a structure is described having two Rgroups that are simultaneously present on the same compound; the two Rgroups can represent different moieties selected from the Markush groupdefined for R. In another example, when an optionally multiplesubstituent is designated in the form:

then it is understood that substituent R can occur s number of times onthe ring, and R can be a different moiety at each occurrence.

As used herein, the term “leaving group” refers to a moiety that can bedisplaced by another moiety, such as by nucleophilic attack, during achemical reaction. Leaving groups are well known in the art and include,for example, halogen including chloro, bromo, iodo, and the like.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C) infrared spectroscopy, spectrophotometry(e.g., UV-visible), or mass spectrometry, or by chromatography such ashigh performance liquid chromatograpy (HPLC) or thin layerchromatography.

In some embodiments, preparation of compounds can involve the protectionand deprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in Greene and Wuts, et al.,Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, 1999,which is incorporated herein by reference in its entirety.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected. In some embodiments, reactionscan be carried out in the absence of solvent, such as when at least oneof the reagents is a liquid or gas.

Suitable solvents can include halogenated solvents such as carbontetrachloride, bromodichloromethane, dibromochloromethane, bromoform,chloroform, bromochloromethane, dibromomethane, butyl chloride,dichloromethane, tetrachloroethylene, trichloroethylene,1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane,2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene,o-dichlorobenzene, chlorobenzene, fluorobenzene, fluorotrichloromethane,chlorotrifluoromethane, bromotrifluoromethane, carbon tetrafluoride,dichlorofluoromethane, chlorodifluoromethane, trifluoromethane,1,2-dichlorotetrafluorethane and hexafluoroethane.

Suitable ether solvents include: dimethoxymethane, tetrahydrofuran,1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethylether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,diethylene glycol diethyl ether, triethylene glycol dimethyl ether,anisole, or t-butyl methyl ether.

Suitable protic solvents can include, by way of example and withoutlimitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol,2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol,2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butylalcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol,neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol. monomethylether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol,phenol, or glycerol.

Suitable aprotic solvents can include, by way of example and withoutlimitation, tetrahydrofuran (THF), dimethylformamide (DMF),dimethylacetamide (DMAC),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethylsulfoxide, propionitrile, ethyl formate, methyl acetate,hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate,sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane,nitrobenzene, or hexamethylphosphoramide.

Suitable hydrocarbon solvents include benzene, cyclohexane, pentane,hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene,m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.

Supercritical carbon dioxide can also be used as a solvent.

The reactions of the processes described herein can be carried out atappropriate temperatures which can be readily determined by the skilledartisan. Reaction temperatures will depend on, for example, the meltingand boiling points of the reagents and solvent, if present; thethermodynamics of the reaction (e.g., vigorously exothermic reactionsmay need to be carried out at reduced temperatures); and the kinetics ofthe reaction (e.g., a high activation energy barrier may need elevatedtemperatures). “Elevated temperature” refers to temperatures above roomtemperature (about 25° C) and “reduced temperature” refers totemperatures below room temperature.

The reactions of the processes described herein can be carried out inair or under an inert atomosphere. Typically, reactions containingreagents or products that are substantially reactive with air can becarried out using air-sensitive synthetic techniques that are well knownto the skilled artisan.

In some embodiments, preparation of compounds can involve the additionof acids or bases to effect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

Example acids can be inorganic or organic acids. Inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, andnitric acid. Organic acids include formic acid, acetic acid, propionicacid, butanoic acid, methanesulfonic acid, p-toluene sulfonic acid,benzenesulfonic acid, trifluoroacetic acid, propiolic acid, butyricacid, 2-butynoic acid, vinyl acetic acid, pentanoic acid, hexanoic acid,heptanoic acid, octanoic acid, nonanoic acid and decanoic acid.

Example bases include lithium hydroxide, sodium hydroxide, potassiumhydroxide, lithium carbonate, sodium carbonate, and potassium carbonate.Some example strong bases include, but are not limited to, hydroxide,alkoxides, metal amides, metal hydrides, metal dialkylamides andarylamines, wherein; alkoxides include lithium, sodium and potassiumsalts of methyl, ethyl and t-butyl oxides; metal amides include sodiumamide, potassium amide and lithium amide; metal hydrides include sodiumhydride, potassium hydride and lithium hydride; and metal dialkylamidesinclude sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, trimethylsilyl and cyclohexyl substituted amides.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis.

The processes described herein can be stereoselective such that anygiven reaction starting with one or more chiral reagents enriched in onestereoisomer forms a product that is also enriched in one stereoisomer.The reaction can be conducted such that the product of the reactionsubstantially retains one or more chiral centers present in the startingmaterials. The reaction can also be conducted such that the product ofthe reaction contains a chiral center that is substantially invertedrelative to a corresponding chiral center present in the startingmaterials.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a “chiral resolving acid” which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asα-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds according to the invention can also include all isotopes ofatoms occurring in the intermediates or final compounds. Isotopesinclude those atoms having the same atomic number but different massnumbers. For example, isotopes of hydrogen include tritium anddeuterium.

Compounds according to the invention can also include tautomeric forms,such as keto-enol tautomers. Tautomeric forms can be in equilibrium orsterically locked into one form by appropriate substitution.

The present invention also includes salt forms of the compoundsdescribed herein. Examples of salts (or salt forms) include, but are notlimited to, mineral or organic acid salts of basic residues such asamines, alkali or organic salts of acidic residues such as carboxylicacids, and the like. Generally, the salt forms can be prepared byreacting the free base or acid with stoichiometric amounts or with anexcess of the desired salt-forming inorganic or organic acid or base ina suitable solvent or various combinations of solvents. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal ofPharmaceutical Science, 66, 2 (1977), each of which is incorporatedherein by reference in its entirety.

Upon carrying out preparation of compounds according to the processesdescribed herein, the usual isolation and purification operations suchas concentration, filtration, extraction, solid-phase extraction,recrystallization, chromatography, and the like may be used, to isolatethe desired products.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES Example 1 Preparation of5-Amino-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile(3)

To a stirred suspension of 2-fluoro-4-methylsulfonylphenyl hydrazine (1)(4.0336 Kg; 1 eq) (commercially available from, e.g., PeakdaleMolecular, Ltd.) in methanol (12.7723 Kg) was added a suspension ofethoxymethylene malononitrile (2.6564 Kg, 1.101 equivalents) in methanol(11.212 Kg) at a rate sufficiently slow to maintain the reaction mixtureat −10° to 0° C. with reactor jacket cooling. After the addition hadbeen completed, the reaction mixture was stirred for 1 hour at −6° C.and then heated to reflux for 5 hours, at which time the reactionmixture gave a pyrazole (3): hydrazine (1) HPLC peak area ratio of105:1. Solvent (20.5153 Kg) was then distilled off the reaction mixtureat atmospheric pressure, leaving a residue having less than 20% of theoriginal volume. The resulting mixture was used directly in the nextstep.

Example 2 Example 2A Preparation of1-(2-fluoro-4-methanesulfonyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(4)

To the concentrated reaction mixture from Example 1 containing pyrazole(3) was added formic acid (36.3924 Kg, 40.0 equivalents) and then water(2.832 Kg) at a rate sufficiently slow to maintain the reaction mixtureat 25° to 35° C. with reactor jacket cooling. After an additional 6.345Kg of solvent had been distilled off the stirred reaction mixture atatmospheric pressure, more formic acid (1.8245 Kg) and then more water(0.564 Kg) were added at a rate sufficiently slow to maintain thereaction mixture at 25° to 35° C. with reactor jacket cooling. A smallamount of remaining volatiles were then distilled off the stirredreaction mixture at atmospheric pressure until a reflux temperature of100° C. was achieved. After six hours of reflux, the reaction mixturegave a product (4):pyrazole (3) HPLC peak area ratio of 670 :1. The onlyother detectable component had an HPLC peak area 0.41% of that forproduct (4). After the reaction mixture is cooled from reflux to 0° C.in 70 minutes, water (10.0 Kg) is added, and the precipitated product isfiltered, washed with 20° C. water (about 40 Kg) until the pH of thewash filtrate is at least 5, and then dried to constant weight at 45°C., ≦40 torr to provide product (4).

Example 2B Preparation of1-(2-fluoro-4-methanesulfonyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (4)

A similar preparation of (4) was carried out where the refluxed reactionmixture was held at a holding temperature of about 70-80° C. overnightafter achieving complete conversion to (4) (>99%). In this preparation,an impurity identified as5-amino-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazole-4-carboxylicacid amide was detected at about 30% (HPLC % peak area). This impurepreparation of 4 containing 4a (5.01 g) was purified by additionalrefluxing in formic acid (25 mL) for about 7 h. After each hour ofrefluxing, a sample was collected. Each sample revealed the presence of4a as well as about an equal amount of1-(2-fluoro-4-methanesulfonyl-phenyl)-5-formylamino-1H-pyrazole-4-carboxylicacid amide; however the total amount of impurity decreased during thecourse of the refluxing until essentially complete conversion wasachieved after 7 hours.

Example 2C Preparation of1-(2-Fluoro-4-methanesulfonyl-phenyl)-1,7-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(4)

To a one liter, bottom discharge jacketed glass reactor equipped withoverhead agitation, reflux condenser and nitrogen blanket bubbler wasadded (2-fluoro-4-methanesulfonyl-phenyl)-hydrazine (50.0 g, 0.244 mol)with the aid of methanol (200 mL, 4 vol Eq.). The resulting reactionmixture was a light slurry and subsequently cooled to −5° C. In aseparate vessel was made a suspension of ethoxymethylene malononitrile(EMM) (32.9 g, 0.270 mol) in methanol (205 mL, 4.1 Vol. Eq.). Theresulting EMM/MeOH suspension was added dropwise to the reactioncontaining (2-fluoro-4-methanesulfonyl-phenyl)-hydrazine at a rate thatmaintains the reaction temperature at about −5C. The reaction mixturewas then held at about −5° C. until all of the starting material((2-fluoro-4-methanesulfonyl-phenyl)-hydrazine) was consumed, typicallyabout 2-4 hrs. The resulting reaction mixture was heated to reflux forabout 2-4 hours until complete conversion to intermediate5-amino-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrile(shown in bracket above) is greater then 99%. The reaction mixture wasthen stripped to near dryness under full house vacuum (<20 torr) with amaximum jacket temperature of 65° C. to afford a soft orange solid. Thesolid was then dissolved in formic acid (250 mL, 5 Vol. Eq.) andsulfuric acid (24.0 g, 0.245 mol) yielding a dark red transparentsolution. The solution was heated to reflux (105-110° C.) and held untilreaction was complete (about 4-5 hrs). The addition of sulfuric acidshowed nearly complete conversion of intermediate5-amino-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazole-4-carbonitrileto another intermediate5-amino-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazole-4-carboxylicacid amide as well as the title compound in one hour with no unknownintermediate (m/z 327 (m+H)⁺ present. The disappearance of5-amino-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazole-4-carboxylicacid amide and appearance of the title compound was then followed untilthe reaction was complete. After the reaction was complete, the reactionmixture was cooled to 65° C. and water (100 mL, 2 Vol Eq.) was slowlyadded to aid in product precipitation. Water was added slowly as it wasslightly exothermic, also rapid addition will make reaction mixture verythick. Slower addition maintains reaction stirrability. Highertemperature additions may alleviate any stirring problems. The reactionwas allowed to stir for 1-2 hrs at 20-25° C. and was filtered.Filtration was quite rapid. Cooling to 0-5° C. may aid in additionalyield. The cake was washed with water (2×100 mL) followed by sodiumbicarbonate (aqueous 5%, 1×150 mL) to neutralize residual acid. Cake wasagain washed with water (1×150 mL) and dried overnight, 65° C., fullhouse vacuum (<20 torr) to afford 67.4 grams of dried light tan/white ofthe title compound @ about 100.0% HPLC purity. The overall molar yieldwas 89.2%.

Example 3 Preparation of 4-Hydroxy-Piperidine-1-Carboxylic AcidIsopropyl Ester (5)

To a stirred mixture of 4-hydroxypiperidine (53.8 g, 1.000 eq),triethylamine (71.8 g, 1.334 equivalents), and ethyl acetate (498.8 g)was added neat isopropyl chloroformate (78.0 g, 1.1966 equivalents) at arate sufficiently slow to maintain the reaction mixture temperature at10°-17° C. with reactor jacket cooling. After the addition had beencompleted, the reaction mixture was stirred at 20° C. for 18 hours. Thenwater (100 g) was added, and the resulting mixture was stirred for 15minutes before the phases were separated. The organic phase was washedwith two 100-gram-portions of 20 wt % aqueous NaCl by stirring for 15min at 150 rpm before separating the aqueous wash. After a final washwith water (100 g), the organic phase was concentrated by distillationon a rotary evaporator at reduced pressure to provide product (2) (91.1g, 92.0 % yield) as light amber oil of 96.8 % purity by GC. Distillationof this crude product at 117-120° C., 0.3-1.0 torr gave a 95.7 %recovery of product (2) as a colorless oil collected at 112°-119° C.

Example 4 Preparation of4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (6)

Diisopropyl azodicarboxylate (2.9812 Kg, 1.1713 equivalents) was addedto a stirred suspension of (4) (3.8806 Kg, 1.000 equivalent),triphenylphosphine (3.8532 Kg, 1.1671 equivalents), and4-methylmorpholine (24.7942 Kg) at a rate sufficiently slow to maintainthe reaction mixture at 20-30° C. with reactor jacket cooling. Theresulting suspension was stirred for 30 minutes at about 25° C. and thenheated to 50-55° C. for about two hours. A solution of4-hydroxypiperidine-1-carboxylic acid isopropyl ester (5) (2.7164 Kg,1.15255 equivalents) in 4-methylmorpholine (3.0302 Kg) was then added tothe reaction mixture at a rate sufficiently slow to maintain thereaction mixture at 45-55° C. About 1.5 hours after the addition of (5)had been completed and then again after another 1.5 hours, moretriphenylphosphine (1.4856 Kg, 0.4500 equivalents and then 0.8897 Kg,0.2695 equivalents) and more diisopropyl azodicarboxylate (1.1445 Kg,0.4497 equivalents and then 0.6894 Kg, 0.2709 equivalents) were added tothe stirred reaction mixture while it continued to be maintained at50-55° C. After about six more hours of stirring at that temperature,the (6):(4) HPLC peak area ratio was greater than 9:1, and the productwas crystallized by cooling the reaction mixture to 0-5° C. and stirringat that temperature for about four hours. The crystallized product wasfiltered, washed with 4-methylmorpholine (4.3802 Kg, 2° C.) and thenwith water (10.4754 Kg, ambient temperature), and then recrystallizedfrom 4-methylmorpholine (20.7215 Kg, about 75° C.) by cooling to 2° C.and stirring at that temperature for about two hours. The recrystallizedproduct was filtered, washed with 4-methylmorpholine (4.5893 Kg, 2° C.)and then with water (10.4955 Kg, ambient temperature), and thenrecrystallized from boiling absolute ethanol (35 Kg) by cooling to 25°C. and stirring at that temperature for about 18 hours. Therecrystallized product was collected by filtration, washed with a 2° C.mixture of absolute ethanol (7.657 Kg) and water (3.8276 Kg), and driedto constant weight at 70° C., ≦40 torr to provide product (6) (3.4269Kg, 57.0% yield).

A similar reaction was conducted using a similar manner as described inthis example except for the use of THF as the solvent and portionwiseaddition of triphenylphosphine, DIAD, and4-hydroxypiperidine-1-carboxylic acid isopropyl ester (5), whichenhanced stirreability and molar efficiency. The multiplecrystallization operation from previous iteration of the technology wasreplaced by a single crystallization in alcohol and aqueous solventmixture which resulted in higher overall yield and consistent purity forproduct (6).

Example 5 Preparation of4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine

POCl₃ (379.1 g, 2.59 mol) was transferred under nitrogen to a 1 L roundbottom flask fitted with a mechanical stirrer, a condenser and a tubeconnected above the condenser filled with a drying agent (drierite).1-(2-Fluoro-4-methanesulfonyl-phenyl)-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one(4) (100 g, 0.324 mol) was added to the reaction vessel, the contentswere stirred, and a slurry was obtained. Dimethylformamide (DMF; 9.43g,0.129 mol) was added, and the reaction mixture was heated to reflux (oilbath set at 130° C.). After refluxing for 3 h, an additional amount ofDMF (9.43 g, 0.129 mol) was added. The resulting mixture was refluxedfor another 2 h and then gradually cooled to 55° C. Subsequently,acetone (270 mL) was added. The mixture was further cooled to 23° C. anda precipitate was obtained, which was isolated by filtration. Thefiltrate was quenched by slow dropwise addition into ice water (1.5 L)with stirring. During the quench, the internal temperature was kept at0° C. or below by cooling with an ice-salt bath. Product4-chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine(7) crystallized out of the quenched mixtures was isolated byfiltration. The solids from both filtrations were combined and washedwith water (2×500 mL), 10% aqueous NaHCO₃ (2×500 mL), and water (2×500mL) until the filtrate was neutral. The washed solids were vacuum driedovernight at room temperature and dissolved in methylene chloride (600mL). The resulting mixture was filtered to remove any residual startingmaterial (4). Hexane (200 mL) was added to the filtrate and methylenechloride was removed by rotary evaporation under reduced pressure.Product crystallized from the hexane solution and was filtered to obtain(7) (95g; 90%). HPLC analysis, 99.26% (purity, by peak area); ¹H NMR(Bruker 400 MHz, CDCl₃) δ 8.88 (s, 1H, Ar—H), 8.46 (s, 1H, Ar—H), 7.96(m, 3H, Ar—H), 3.14 (s, 3H, —SO₂CH₃); mass spec. (electrospray), m/z 327(M+H).

Example 6 Alternate preparation of4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (6)

Toluene (1.6 L) was transferred to a 4 L jacketed reaction vessel fittedwith a mechanical stirrer, nitrogen inlet and a temperature probe.4-Chloro-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine(7) (97.0g, 0.297 mol) was added with stirring into the reaction vesselunder nitrogen, and a slurry was obtained. The carbamate,4-hydroxy-piperidine-1-carboxylic acid isopropyl ester (5) (66.57g,0.356 mol), was added at room temperature. The reactor was cooled to 12°C. and sodium tert-butoxide (37.09g, 0.386 mol) was added with stirring.The internal temperature gradually increased to 34° C. due to anexotherm. Then the internal temperature was brought down to 23-25° C.The reaction mixture became a thick slurry and was stirred at roomtemperature for 2.5 h. The precipitate from the reaction mixture wasfiltered, washed with toluene (250 mL) followed by water (3×500 mL), andvacuum dried overnight at room temperature. The dried solid product wasslurried in EtOH (500 mL) at room temperature, filtered, and washed withwater (2.5 L) until the filtrate was neutral. The washed solid productwas dissolved in refluxing EtOH (1.3 L), and the resulting clearsolution was gradually cooled to room temperature. The product (6)crystallized out and was isolated by filtration and dried overnight in avacuum oven at 40° C., 20 torr to provide 105.5 g of product (6) (74%).HPLC analysis, >99% (purity, by peak area). ¹H NMR (Bruker 400 MHz,CDCl₃) δ 8.62 (s, 1H, Ar—H), 8.32 (s, 1H, Ar—H), 7.93 (m, 3H, Ar—H),5.62 (m, 1H, —O—CH—), 4.95 (m, 1H, CH₃—CH—CH₃), 3.91 (m, 2H, —CH₂—),3.37 (m, 2H, —CH₂—), 3.12 (s, 3H, —SO₂CH₃), 2.09 (m, 2H, —CH₂—), 1.87(m, 2H, —CH₂—), 1.27 (d, 6H, J=8 Hz, CH ₃—CH—CH ₃); mass spec.(electrospray) m/z 478 (M+H).

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference cited in the presentapplication is incorporated herein by reference in its entirety.

1. A process for preparing a compound of Formula I:

wherein: R¹ is C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl,or halogen; R² is —R²⁴, —CR²⁵R²⁶C(O)—R²⁴, —C(O)CR²⁵R²⁶—R²⁴, —C(O)—R²⁴,—CR²⁵R²⁶C(O)NR²⁷—R²⁴, —NR²⁷C(O)CR²⁵R²⁶—R²⁴, —C(O)NR²⁵—R²⁴,—NR²⁵C(O)—R²⁴, —C(O)O—R²⁴, —OC(O)—R²⁴, —C(S)—R²⁴, —C(S)NR²⁵—R²⁴,—NR²⁵C(S)—R²⁴, —C(S)O—R²⁴, —OC(S)—R²⁴, —CR²⁵R²⁶—R²⁴, or —S(O)₂—R ²⁴; R³is H, C₁₋₈ alkyl or C₃₋₇ cycloalkyl, wherein said C₁₋₈ alkyl isoptionally substituted with C₁₋₄ alkoxy, C₃₋₇ cycloalkyl, or heteroaryl;R⁵ and R¹⁰ are each, independently, H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino,carboxamide, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylsulfonamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl,hydroxylamino or nitro; wherein said C₂₋₆ alkenyl, C₁₋₈ alkyl, C₂₋₆alkynyl and C₃₋₆ cycloalkyl are optionally substituted with 1, 2, 3 or 4substituents selected from C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₄alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino andnitro; R¹³ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, arylsulfonyl,carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, dialkylthiocarboxamide, guanidinyl, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclic, heterocyclic-oxy,heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl,heteroarylcarbonyl, hydroxyl, nitro, C₄₋₇ oxo-cycloalkyl, phenoxy,phenyl, sulfonamide, sulfonic acid, or thiol; and wherein said C₁₋₅acyl, C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino,C₁₋₆ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, arylsulfonyl,carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic, heterocyclic-carbonyl,heteroaryl, phenoxy and phenyl are optionally substituted with 1 to 5substituents selected from C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino,C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,heteroaryl, heterocyclic, hydroxyl, nitro, phenyl, and phosphonooxy; andwherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are each optionallysubstituted with 1 to 5 substituents selected from C₁₋₄ alkoxy andhydroxy; or R¹³ is a group of Formula (A):

R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each, independently, H, C₁₋₅ acyl, C₁₋₅acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide,C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl or nitro; or twoadjacent R¹⁴, R¹⁵, R¹⁶ and R¹⁷ together with the atoms to which they areattached form a 5-, 6- or 7-membered fused cycloalkyl, cycloalkenyl orheterocyclic group, wherein said 5-, 6- or 7-membered fused group isoptionally substituted with halogen; R¹⁸ is H, C₁₋₅ acyl, C₂₋₆ alkenyl,C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆dialkylcarboxamide, halogen, heteroaryl or phenyl, and wherein saidheteroaryl or phenyl is optionally substituted with 1 to 5 substituentsselected independently from C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆alkynyl, C₂₋₈ dialkylamino, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl andhydroxyl; R²⁴ is H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, orheterocyclic each optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, heterocyclic, hydroxyl, hydroxylamino, nitro, phenyl,phenoxy, and sulfonic acid, wherein said C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylamino, heteroaryl, phenyl and phenoxy are each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino,C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide,C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄alkylthioureyl, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino, nitro, and phenyl; R²⁵, R²⁶ and R²⁷ are each,independently, H or C₁₋₈ alkyl; m is 0, 1, 2, 3, or 4; n is 0 or 1; andp and r are each, independently, 0, 1, 2 or 3; said process comprisingreacting a compound of Formula II:

with a compound of Formula III:

in the presence of a trisubstituted phosphine and a compound having theFormula A′:

wherein R′ and R″ are each, independently, C₁₋₁₀ alkyl or C₃₋₇cycloalkyl; to form the compound of Formula I.
 2. The process of claim 1wherein said trisubstituted phosphine is triphenylphosphine.
 3. Theprocess of claim 1 wherein R′ and R″ are both prop-2-yl.
 4. The processof claim 1 wherein said phosphine is added in two or more portions. 5.The process of claim 1 wherein said compound of Formula A is added intwo or more portions.
 6. The process of claim 1 wherein said reacting iscarried out at a temperature of about 35 to about 65° C.
 7. The processof claim 1 wherein said reacting is carried out in a solvent.
 8. Theprocess of claim 7 wherein said tertiary amine is 4-methylmorpholine. 9.The process of claim 7 wherein said ether solvent is THF.
 10. Theprocess of claim 1 wherein the molar ratio of compound of Formula A′ tocompound of Formula II is about 2:1 to about 1:1.
 11. The process ofclaim 1 wherein the molar ratio of trisubstituted phosphine to compoundof Formula II is about 2:1 to about 1:1.
 12. The process of claim 1wherein the molar ratio of compound of Formula II to compound of FormulaIII is about 1:1.
 13. The process of claim 1 wherein: R² is —C(O)O—R²⁴;R³ is H; R⁵ is H; R¹⁰ is H; R¹³ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, arylsulfonyl,carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, dialkylthiocarboxamide, guanidinyl, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclic, heterocyclic-oxy,heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl,heteroarylcarbonyl, hydroxyl, nitro, C₄₋₇ oxo-cycloalkyl, phenoxy,phenyl, sulfonamide, sulfonic acid, or thiol; R¹⁴, R¹⁵, R¹⁶, and R¹⁷ areeach, independently, H, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₂₋₆alkynyl, cyano, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, hydroxyl, ornitro; n is 1; and m is
 0. 14. The process of claim 1 wherein: R² is—C(O)O—R²⁴; R³ is H; R⁵is H; R¹⁰ is H; R¹³ is methylsulfonyl; R¹⁴ is F;R¹⁵, R¹⁶, and R¹⁷ are each H; R²⁴ is prop-2-yl; n is 1; and m is
 0. 15.The process of claim 1 wherein said compound of Formula II is preparedby the method comprising reacting a compound of Formula IV:

with R⁵CO₂H to form said compound of Formula II.
 16. The process ofclaim 15 further comprising sulfuric acid.
 17. The process of claim 15wherein said reacting of said compound of Formula IV is carried out inthe presence of aqueous solvent.
 18. The process of claim 15 whereinsaid reacting of said compound of Formula IV is carried out at atemperature of about 80 to about 120° C.
 19. The process of claim 15wherein R⁵CO₂H is provided in molar excess relative to said compound ofFormula IV.
 20. The process of claim 15 wherein R⁵ is H.
 21. The processof claim 15 wherein said compound of Formula IV is prepared by themethod comprising reacting a compound of Formula V:

with a compound of Formula VI:

wherein R is C₁₋₄ alkyl; to form said compound of Formula IV.
 22. Theprocess of claim 21 wherein said reacting of compound of Formula V iscarried out in an alcohol.
 23. The process of claim 22 wherein saidalcohol is methanol.
 24. The process of claim 21 wherein said reactingof said compound of Formula V is carried out in the absence of a base.25. The process of claim 21 wherein the molar ratio of said compound ofFormula V to said compound of Formula VI is about 1:1.
 26. The processof claim 21 wherein said compound of Formula V and said compound ofFormula VI are combined at a temperature of about −20 to about 10° C.27. The process of claim 21 wherein R is methyl or ethyl.
 28. Theprocess of claim 21 wherein R¹⁰ is H.
 29. A process for preparing acompound of Formula II:

wherein: R⁵ and R¹⁰ are each, independently, H, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl,C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino,carboxamide, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylsulfonamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl,hydroxylamino or nitro; wherein said C₂₋₆ alkenyl, C₁₋₈ alkyl, C₂₋₆alkynyl and C₃₋₆ cycloalkyl are optionally substituted with 1, 2, 3 or 4substituents selected from C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₄alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino andnitro; R¹³ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, arylsulfonyl,carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, dialkylthiocarboxamide, guanidinyl, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclic, heterocyclic-oxy,heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl,heteroarylcarbonyl, hydroxyl, nitro, C₄₋₇ oxo-cycloalkyl, phenoxy,phenyl, sulfonamide, sulfonic acid, or thiol; and wherein said C₁₋₅acyl, C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino,C₁₋₆ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, arylsulfonyl,carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic, heterocyclic-carbonyl,heteroaryl, phenoxy and phenyl are optionally substituted with 1 to 5substituents selected from C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino,C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,heteroaryl, heterocyclic, hydroxyl, nitro, phenyl, and phosphonooxy; andwherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are each optionallysubstituted with 1 to 5 substituents selected from C₁₋₄ alkoxy andhydroxy; or R¹³ is a group of Formula (A):

R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each, independently, H, C₁₋₅ acyl, C₁₋₅acyloxy, C₂₋₆ C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl or nitro; or twoadjacent R¹⁴, R¹⁵, R¹⁶ and R¹⁷ together with the atoms to which they areattached form a 5-, 6- or 7-membered fused cycloalkyl, cycloalkenyl orheterocyclic group, wherein said 5-, 6- or 7-membered fused group isoptionally substituted with halogen; R¹⁸ is H, C₁₋₅ acyl, C₂₋₆ alkenyl,C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆dialkylcarboxamide, halogen, heteroaryl or phenyl, and wherein saidheteroaryl or phenyl is optionally substituted with 1 to 5 substituentsselected independently from C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆alkynyl, C₂₋₈ dialkylamino, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl andhydroxyl; and p and r are each, independently, 0, 1, 2 or 3; comprising:a) reacting a compound of Formula V:

with a compound of Formula VI:

wherein R is C₁₋₄ alkyl; in the absence of base to form said compound ofFormula IV; and b) reacting said compound of Formula IV with R⁵CO₂H toform said compound of Formula II.
 30. The process of claim 29 whereinsaid reacting of compound of Formula V is carried out in an alcohol. 31.The process of claim 30 wherein said alcohol is methanol.
 32. Theprocess of claim 29 wherein the molar ratio of said compound of FormulaV to said compound of Formula VI is about 1:1.1.
 33. The process ofclaim 29 wherein said compound of Formula V and said compound of FormulaVI are combined at a temperature of about −20 to about 10° C.
 34. Theprocess of claim 29 wherein R is methyl or ethyl.
 35. The process ofclaim 29 wherein R¹⁰ is H.
 36. The process of claim 29 wherein saidreacting of said compound of Formula IV is carried out in the presenceof aqueous solvent.
 37. The process of claim 29 wherein said reacting ofsaid compound of Formula IV is carried out at a temperature of about 80to about 120° C.
 38. The process of claim 29 wherein said R⁵CO₂H isprovided in molar excess relative to said compound of Formula IV. 39.The process of claim 29 wherein R⁵ is H.
 40. A process for preparing acompound of Formula IV:

wherein: R¹⁰ is H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl,C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, carboxamide, cyano, C₃₋₆cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl, hydroxylamino or nitro;wherein said C₂₋₆ alkenyl, C₁₋₈ alkyl, C₂₋₆ alkynyl and C₃₋₆ cycloalkylare optionally substituted with 1, 2, 3 or 4 substituents selected fromC₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide,C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino andnitro; R¹³ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, arylsulfonyl,carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, dialkylthiocarboxamide, guanidinyl, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclic, heterocyclic-oxy,heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl,heteroarylcarbonyl, hydroxyl, nitro, C₄₋₇ oxo-cycloalkyl, phenoxy,phenyl, sulfonamide, sulfonic acid, or thiol; and wherein said C₁₋₅acyl, C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino,C₁₋₆ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, arylsulfonyl,carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic, heterocyclic-carbonyl,heteroaryl, phenoxy and phenyl are optionally substituted with 1 to 5substituents selected from C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino,C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,heteroaryl, heterocyclic, hydroxyl, nitro, phenyl, and phosphonooxy; andwherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are each optionallysubstituted with 1 to 5 substituents selected from C₁₋₄ alkoxy andhydroxy; or R¹³ is a group of Formula (A):

R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each, independently, H, C₁₋₅ acyl, C₁₋₅acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide,C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl or nitro; or twoadjacent R¹⁴, R¹⁵, R¹⁶ and R¹⁷ together with the atoms to which they areattached form a 5-, 6- or 7-membered fused cycloalkyl, cycloalkenyl orheterocyclic group, wherein said 5-, 6- or 7-membered fused group isoptionally substituted with halogen; R¹⁸ is H, C₁₋₅ acyl, C₂₋₆ alkenyl,C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆dialkylcarboxamide, halogen, heteroaryl or phenyl, and wherein saidheteroaryl or phenyl is optionally substituted with 1 to 5 substituentsselected independently from C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆alkynyl, C₂₋₈ dialkylamino, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl andhydroxyl; and p and r are each, independently, 0, 1, 2 or 3; comprisingreacting a compound of Formula V:

with a compound of Formula VI:

wherein R is C₁₋₄ alkyl; in the absence of base, to form said compoundof Formula IV.
 41. The process of claim 40 wherein said reacting ofcompound of Formula V is carried out in an alcohol.
 42. The process ofclaim 40 wherein said alcohol is methanol.
 43. The process of claim 40wherein the molar ratio of said compound of Formula V to said compoundof Formula VI is about 1:1.1.
 44. The process of claim 40 wherein saidcompound of Formula V and said compound of Formula VI are combined at atemperature of about −20 to about 10° C.
 45. The process of claim 40wherein R is methyl or ethyl.
 46. The process of claim 40 wherein R¹⁰ isH.
 47. A process for preparing a compound of Formula I:

wherein: R¹ is C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl,or halogen; R² is —R²⁴, —CR²⁵R²⁶C(O)—R²⁴, —C(O)CR²⁵R²⁶—R²⁴, —C(O)—R²⁴,—CR²⁵R²⁶C(O)NR²⁷—R²⁴, —NR²⁷C(O)CR²⁵R²⁶—R²⁴, —C(O)NR²⁵—R²⁴,—NR²⁵C(O)—R²⁴, —C(O)O—R²⁴, —OC(O)—R²⁴, —C(S)—R²⁴, —C(S)NR²⁵—R²⁴,—NR²⁵C(S)—R²⁴, —C(S)O—R²⁴, —OC(S)—R²⁴, —CR²⁵R²⁶—R²⁴, or —S(O)₂—R²⁴; R³is H, C₁₋₈ alkyl or C₃₋₇ cycloalkyl, wherein said C₁₋₈ alkyl isoptionally substituted with C₁₋₄ alkoxy, C₃₋₇ cycloalkyl, or heteroaryl;R⁵ and R¹⁰ are each, independently, H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino,carboxamide, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylsulfonamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl,hydroxylamino or nitro; wherein said C₂₋₆ alkenyl, C₁₋₈ alkyl, C₂₋₆alkynyl and C₃₋₆ cycloalkyl are optionally substituted with 1, 2, 3 or 4substituents selected from C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₄alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino andnitro; R¹³ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, arylsulfonyl,carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, guanidinyl, halogen,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclic, heterocyclic-oxy,heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl,heteroarylcarbonyl, hydroxyl, nitro, C₄₋₇ oxo-cycloalkyl, phenoxy,phenyl, sulfonamide, sulfonic acid, or thiol; and wherein said C₁₋₅acyl, C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino,C₁₋₆ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, arylsulfonyl,carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic, heterocyclic-carbonyl,heteroaryl, phenoxy and phenyl are optionally substituted with 1 to 5substituents selected from C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino,C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,heteroaryl, heterocyclic, hydroxyl, nitro, phenyl, and phosphonooxy; andwherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are each optionallysubstituted with 1 to 5 substituents selected from C₁₋₄ alkoxy andhydroxy; or R¹³ is a group of Formula (A):

R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each, independently, H, C₁₋₅ acyl, C₁₋₅acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide,C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl or nitro; or twoadjacent R¹⁴, R¹⁵, R¹⁶ and R¹⁷ together with the atoms to which they areattached form a 5-, 6- or 7-membered fused cycloalkyl, cycloalkenyl orheterocyclic group, wherein said 5-, 6- or 7-membered fused group isoptionally substituted with halogen; R¹⁸ is H, C₁₋₅ acyl, C₂₋₆ alkenyl,C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆dialkylcarboxamide, halogen, heteroaryl or phenyl, and wherein saidheteroaryl or phenyl is optionally substituted with 1 to 5 substituentsselected independently from C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆alkynyl, C₂₋₈ dialkylamino, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl andhydroxyl; R²⁴ is H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, orheterocyclic each optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, heterocyclic, hydroxyl, hydroxylamino, nitro, phenyl,phenoxy, and sulfonic acid, wherein said C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylamino, heteroaryl, phenyl and phenoxy are each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino,C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide,C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄alkylthioureyl, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino, nitro, and phenyl; R²⁵, R²⁶ and R²⁷ are each,independently, H or C₁₋₈ alkyl; m is 0, 1, 2, 3, or 4; n is 0 or 1; andp and r are each, independently, 0, 1, 2 or 3; said process comprisingreacting a compound of Formula IIa:

wherein X is halo; with a compound of Formula III:

in the presence of an alkoxide salt, to form said compound of Formula I.48. The process of claim 47 wherein said alkoxide salt is a methoxide,ethoxide, propoxide, isopropoxide, n-butoxide, isobutoxide, ort-butoxide salt.
 49. The process of claim 47 wherein said alkoxide saltsodium t-butoxide.
 50. The process of claim 47 wherein said reacting iscarried out in a solvent.
 51. The process of claim 50 wherein saidsolvent comprises toluene.
 52. The process of claim 47 wherein saidreacting is carried out at a temperature below about 30° C.
 53. Theprocess of claim 47 wherein the molar ratio of said compound of FormulaIII to said compound of Formula IIa is about 2:1 to about 1:1.
 54. Theprocess of claim 47 wherein the molar ratio of alkoxide salt to saidcompound of Formula IIa is about 2:1 to about 1:1.
 55. The process ofclaim 47 wherein X is Cl.
 56. The process of claim 47 wherein: R² is—C(O)O—R²⁴; R³ is H; R⁵ is H; R¹⁰ is H; R¹³ is C₁₋₅ acyl, C₁₋₆acylsulfonamide, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl,C₁₋₄ alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,arylsulfonyl, carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, guanidinyl, halogen,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclic, heterocyclic-oxy,heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl,heteroarylcarbonyl, hydroxyl, nitro, C₄₋₇ oxo-cycloalkyl, phenoxy,phenyl, sulfonamide, sulfonic acid, or thiol; R¹⁴, R¹⁵, R¹⁶, and R¹⁷ areeach, independently, H, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₂₋₆alkynyl, cyano, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, hydroxyl, ornitro; n is 1; and m is
 0. 57. The process of claim 47 wherein: R² is—C(O)O—R²⁴; R³ is H; R⁵ is H; R¹⁰ is H; R¹³ is methylsulfonyl; R¹⁴ is F;R¹⁵, R¹⁶, and R¹⁷ are each H; R²⁴ is prop-2-yl; n is 1; and m is
 0. 58.The process of claim 47 wherein said compound of Formula IIa is preparedby a method comprising reacting a compound of Formula II:

with a halogenating reagent to form said compound of Formula IIa. 59.The process of claim 58 wherein said halogenating reagent is achlorinating reagent.
 60. The process of claim 58 wherein saidhalogenating reagent is POCl₃.
 61. The process of claim 58 wherein saidreacting of said compound of Formula II with a halogenating reagent iscarried out in the presence of a catalyst.
 62. The process of claim 61wherein said catalyst is dimethylformamide.
 63. The process of claim 58wherein said reacting of said compound of Formula II is carried out at atemperature of about 80 to about 140° C.
 64. The process of claim 58wherein the molar ratio of halogenating reagent to the amount ofcompound of Formula II is about 50:1 to about 2:1.
 65. The process ofclaim 58 wherein the molar ratio of compound of Formula II to amount ofcatalyst is about 1.3:1 to about 1.2:1.
 66. A process for preparing acompound of Formula I:

wherein: R¹ is C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl,or halogen; R² is —R²⁴, —CR²⁵R²⁶C(O)—R²⁴, —C(O)CR²⁵R²⁶—R²⁴, —C(O)—R²⁴,—CR²⁵R²⁶C(O)NR²⁷—R²⁴, —NR²⁷C(O)CR²⁵R²⁶—R²⁴, —C(O)NR²⁵—R²⁴,—NR²⁵C(O)—R²⁴, —C(O)O—R²⁴, —OC(O)—R²⁴, —C(S)—R²⁴, —C(S)NR²⁵—R²⁴,—NR²⁵C(S)—R²⁴, —C(S)O—R²⁴, —OC(S)—R²⁴, —CR²⁵R²⁶—R²⁴, or —S(O)₂—R²⁴; R³is H, C₁₋₈ alkyl or C₃₋₇ cycloalkyl, wherein said C₁₋₈ alkyl isoptionally substituted with C₁₋₄ alkoxy, C₃₋₇ cycloalkyl, or heteroaryl;R⁵ and R¹⁰ are each, independently, H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino,carboxamide, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylsulfonamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl,hydroxylamino or nitro; wherein said C₂₋₆ alkenyl, C₁₋₈ alkyl, C₂₋₆alkynyl and C₃₋₆ cycloalkyl are optionally substituted with 1, 2, 3 or 4substituents selected from C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₄alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino andnitro; R¹³ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, arylsulfonyl,carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, guanidinyl, halogen,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclic, heterocyclic-oxy,heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl,heteroarylcarbonyl, hydroxyl, nitro, C₄₋₇ oxo-cycloalkyl, phenoxy,phenyl, sulfonamide, sulfonic acid, or thiol; and wherein said C₁₋₅acyl, C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino,C₁₋₆ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, arylsulfonyl,carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic, heterocyclic-carbonyl,heteroaryl, phenoxy and phenyl are optionally substituted with 1 to 5substituents selected from C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino,C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,heteroaryl, heterocyclic, hydroxyl, nitro, phenyl, and phosphonooxy; andwherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are each optionallysubstituted with 1 to 5 substituents selected from C₁₋₄ alkoxy andhydroxy; or R¹³ is a group of Formula (A):

R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each, independently, H, C₁₋₅ acyl, C₁₋₅acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide,C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl or nitro; or twoadjacent R¹⁴, R¹⁵, R¹⁶ and R¹⁷ together with the atoms to which they areattached form a 5-, 6- or 7-membered fused cycloalkyl, cycloalkenyl orheterocyclic group, wherein said 5-, 6- or 7-membered fused group isoptionally substituted with halogen; R ¹⁸is H, C₁₋₅ acyl, C₂₋₆ alkenyl,C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆dialkylcarboxamide, halogen, heteroaryl or phenyl, and wherein saidheteroaryl or phenyl is optionally substituted with 1 to 5 substituentsselected independently from C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆alkynyl, C₂₋₈ dialkylamino, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl andhydroxyl; R²⁴ is H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, orheterocyclic each optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, heterocyclic, hydroxyl, hydroxylamino, nitro, phenyl,phenoxy, and sulfonic acid, wherein said C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄alkylamino, heteroaryl, phenyl and phenoxy are each optionallysubstituted with 1 to 5 substituents selected from the group consistingof C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino,C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide,C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄alkylthioureyl, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino, nitro, and phenyl; R²⁵, R²⁶ and R²⁷ are each,independently, H or C₁₋₈ alkyl; m is 0, 1, 2, 3, or 4; n is 0 or 1; andp and r are each, independently, 0, 1, 2 or 3; said process comprising:a) reacting a compound of Formula II:

with a halogenating reagent in the presence of a catalyst to form acompound of Formula IIa.

wherein X is halo; and b) reacting said compound of Formula IIa with acompound of Formula III:

in the presence of an alkoxide salt, to form said compound of Formula I.67. A process for preparing a compound of Formula IIa:

wherein: X is halo; R⁵ and R¹⁰ are each, independently, H, C₁₋₅ acyloxy,C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈dialkylamino, carboxamide, cyano, C₃₋₆ cycloalkyl, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkylthio, hydroxyl, hydroxylamino or nitro; wherein said C₂₋₆alkenyl, C₁₋₈ alkyl, C₂₋₆ alkynyl and C₃₋₆ cycloalkyl are optionallysubstituted with 1, 2, 3 or 4 substituents selected from C₁₋₅ acyl, C₁₋₅acyloxy, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₂₋₈dialkylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino andnitro; R¹³ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, arylsulfonyl,carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, guanidinyl, halogen,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclic, heterocyclic-oxy,heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl,heteroarylcarbonyl, hydroxyl, nitro, C₄₋₇ oxo-cycloalkyl, phenoxy,phenyl, sulfonamide, sulfonic acid, or thiol; and wherein said C₁₋₅acyl, C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino,C₁₋₆ alkylsulfonamide, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, arylsulfonyl,carbamimidoyl, C₂₋₆ dialkylamino, heterocyclic, heterocyclic-carbonyl,heteroaryl, phenoxy and phenyl are optionally substituted with 1 to 5substituents selected from C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino,C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,heteroaryl, heterocyclic, hydroxyl, nitro, phenyl, and phosphonooxy; andwherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are each optionallysubstituted with 1 to 5 substituents selected from C₁₋₄ alkoxy andhydroxy; or R¹³ is a group of Formula (A):

R¹⁴, R¹⁵, R¹⁶, and R¹⁷ are each, independently, H, C₁₋₅ acyl, C₁₋₅acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide,C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl or nitro; or twoadjacent R¹⁴, R¹⁵, R¹⁶ and R¹⁷ together with the atoms to which they areattached form a 5-, 6- or 7-membered fused cycloalkyl, cycloalkenyl orheterocyclic group, wherein said 5-, 6- or 7-membered fused group isoptionally substituted with halogen; R¹⁸ is H, C₁₋₅ acyl, C₂₋₆ alkenyl,C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆dialkylcarboxamide, halogen, heteroaryl or phenyl, and wherein saidheteroaryl or phenyl is optionally substituted with 1 to 5 substituentsselected independently from C₁₋₄ alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆alkynyl, C₂₋₈ dialkylamino, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl andhydroxyl; p and r are each, independently, 0, 1, 2 or 3; said processcomprising reacting a compound of Formula II:

with a halogenating reagent in the presence of a di-substituted amidecatalyst to form said compound of Formula IIa.
 68. The process of claim67 wherein said halogenating reagent is a chlorinating reagent.
 69. Theprocess of claim 67 wherein said halogenating reagent is POCl₃.
 70. Theprocess of claim 67 wherein said catalyst comprises dimethylformamide.71. The process of claim 67 wherein said reacting of said compound ofFormula II is carried out at a temperature of about 80 to about 140° C.72. The process of claim 67 wherein the molar ratio of halogenatingreagent to the amount of compound of Formula II is about 50:1 to about2:1.
 73. The process of claim 67 wherein the molar ratio of compound ofFormula II to amount of catalyst is about 1.3:1 to about 1.2:1.